Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

• the present invention relates to new derivatives of 1H, 3H-pyrrolo [1,2-c] thiazole of general formula: in which R represents a hydrogen or halogen atom or an alkyl, alkyloxy, alkylthio, trifluoromethyl, amino, alkyllamino, dialcoylamino, hydroxy, cyano, carboxy, alkylsulfinyl, alkylsulphonyl, sulfamido, alkylsulboyl, carboyloyl, dialkoylcarbamoyl, phenylcarbamoyl, diphenylcarbamoyl, pyridylcarbamoyl, dipyridylcarbamoyl, benzyl, alkylcarbonyl, benzoyl, alkoyloxycarbonyl, phenoxycarbonyl, alkoylcarbonyloxy, benzoyloxy, benzoyloxy, pheno
• the products of general formula (I) can be prepared by the action of an amine of general formula: in which R, X and Ar are defined as above on an acid of formula: or a reactive derivative of this acid.
• the acid chloride and to carry out the reaction in an organic solvent such as chloroform, methylene chloride or dioxane at a temperature between 0 ° C and the reflux temperature of the reaction mixture , in the presence of an acid acceptor such as triethylamine.
• organic solvent such as chloroform, methylene chloride or dioxane
• the acid of racemic formula (III) can be prepared according to the method described in European patent No. 0 115 979.
• the amines of general formula (II) can be prepared by application or adaptation of the methods already described in the literature.
• the saponification is carried out by any gentle method known to a person skilled in the art to transform an ester into an acid without racemizing the chiral centers present in the molecule. It is particularly advantageous to carry out the saponification using an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide at a temperature between 20 and 50 ° C.
• an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide at a temperature between 20 and 50 ° C.
• the ester of general formula (IV) can be obtained by reacting the reaction product of p-toluene sulfonyl chloride, triethylamine and the acid of formula: in which the symbol * has the same meaning as in the corresponding ester (IV) defined above on the reaction product of triethylamine and an 2,3-dichloro-alkyl propionate of general formula: wherein R 'is defined as above, in an organic solvent such as 1,2-dichloroethane or methylene chloride at a temperature between 20 ° C and the reflux temperature of the reaction mixture.
• an organic solvent such as 1,2-dichloroethane or methylene chloride
• the products of general formula (I), dextrorotatory, levorotatory or racemic can also be prepared by reacting the reaction product of p-toluenesulfonyl chloride, triethylamine and dextrorotatory, levorotatory or racemic acid. correspondent of formula (V) on the reaction product of triethylamine and of a product of general formula: in which the symbols are defined as above.
• the products of general formula (VII T ) can be prepared by application or adaptation of methods known in the literature, in particular by the action of 2,3-dichloro propionyl chloride on an amine of general formula (II) defined as above, in operating in toluene at a temperature between 20 ° C and the reflux temperature of the reaction mixture.
• the new products of general formula (I) can be transformed into an addition salt with acids by the action of an acid in an organic solvent such as an alcohol, a ketone, an ether or a chlorinated solvent.
• the salt precipitates, generally after concentration of its solution; it is separated by filtration or decantation.
• the new products of general formula (I) containing an acid group in their molecule can be transformed into metal salts or into addition salts with nitrogenous bases, by any method known to a person skilled in the art for carrying out this salification without affecting the rest of the molecule.
• the buffer A described above is successively introduced, the product to be studied, the tritiated PAF-acether (0.5 nMole - specific activity: 80 Ci / mMole) and the platelets obtained as described above (0, 5.10 $ platelets), so as to obtain a final volume of 0.5 cm3 and the mixture is left to incubate for one hour at 20 ° C.
• 2 cm3 of buffer A cooled to 4 ° C. are then added, the contents of the tube are rapidly filtered on a WHATMAN GF / C (registered trademark) filter and the tube is rinsed very quickly 3 times with 2 cm3 of buffer A cooled to 4 ° C.
• the filter is dried and placed in a flask containing 4.5 cm3 of READY SOLV scintillating liquid. MP (ND BECKMAN) and the radioactivity is measured using a universal counter RACK BETA 1218 LKB. The total bound radioactivity is thus determined.
• the specific binding of the tritiated PAF-acether is determined by subtracting from the total bound radioactivity, the radioactivity remaining on the filter after addition of 10 ⁇ mol of N- (3-methoxyphenyl) (pyridyl-3) -3 1H, 3H-pyrrolo 1,2 - c] thiazolecarboxamide-7. For each product to be studied, the test is repeated 3 times at increasing concentrations ranging from 10 -10 to 10 -4 M.
• the IC 50 is determined graphically for each product by log probit analysis of the inhibition curve.
• PAF-acether is involved in a large number of diseases and disorders such as allergic reactions (asthma or bronchitis) or inflammatory reactions of the gastric and intestinal mucous membranes of various origins and in particular inflammatory reactions due to irradiation and to endotoxin shocks as well as disorders related to platelet aggregation.
• the PAF-acether released during these disorders binds to specific receptors for this mediator.
• the blood platelet receptor binding test described above, is one of the possible experimental models to study the ability of products to bind to these. receivers.
• the products according to the invention displace PAF-acether from its binding sites. They therefore compete with it and antagonize its effects. Thus, it is foreseeable that the products according to the invention will have a therapeutic role in the treatment of the diseases and conditions listed above.
• European patent 0 115 979 already discloses pyrrolothiazoles which have a certain inhibitory action with respect to PAF-acether but the products according to the present invention bind to the platelet receptors at much lower doses and are therefore more able to inhibit the effects of PAF-acether.
• the products according to the invention have a low toxicity.
• Their LD 50 is generally between 300 and 900 mg / kg in the oral mouse.
• R represents a hydrogen or halogen atom or an alkyloxy or dialkoylamino radical
• X represents an oxygen or sulfur atom or an imino, carbonyl, carbonylmethylene radical, vinylenecarbonyl or else represents a methylene radical
• Ar represents a phenyl, naphthyl, pyridyl, 2-thienyl radical, these radicals possibly being unsubstituted or substituted by a halogen atom or an alkyl, alkyloxy, dialkoylamino, carboxy or alkyloxycarbonyl radical, being understood that the alkyl radicals and alkyl portions contain 1 to 4 carbon atoms in a straight or branched chain and that the products concerned are the racemic products, the enantiomers due to the presence of an asymmetric carbon in position 3 of the pyrrolothiazole ring and the mixtures of these enantiomers.
• R represents a hydrogen atom
• X represents an oxygen atom or a carbonyl radical
• Ar represents a phenyl or pyridyl radical
• these radicals being able to be unsubstituted or substituted by a halogen atom or an alkyl or alkyloxy radical
• the alkyl radicals and alkyl portions contain 1 to 4 carbon atoms in a straight or branched chain and that the products concerned are the racemic products, the enantiomers due to the presence of an asymmetric carbon in position 3 of the pyrrolothiazole cycle and mixtures of these enantiomers.
• the products according to the invention which are the most interesting are those which are in the racemic form and the optical isomers of dextrorotatory form.
• salts As pharmaceutically acceptable salts, mention may be made of addition salts with mineral acids such as hydrochlorides, sulfates, nitrates, phosphates or organic salts such as acetates, propionates, succinates, benzoates, fumarates, maleates, methanesulfonates, isethionates, theophillineacetates, salicylates, phenolphthalinates , methylene-bis-p-oxynaphtoates or substitution derivatives of these compounds.
• mineral acids such as hydrochlorides, sulfates, nitrates, phosphates or organic salts such as acetates, propionates, succinates, benzoates, fumarates, maleates, methanesulfonates, isethionates, theophillineacetates, salicylates, phenolphthalinates , methylene-bis-p-oxynaphtoates or substitution derivatives of these compounds.
• salts with alkali metals such as the sodium, potassium or lithium salts
• alkaline earth metals such as the calcium or magnesium salts
• addition salts with organic bases such as the ethanolamine or lysine salts.
• the solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C.
• the residue is dissolved in 250 cm3 of methylene chloride and the solution obtained is washed 2 times with 200 cm3 in total of distilled water, 2 times with 200 cm3 in total with a 4N aqueous sodium hydroxide solution and 2 times with 200 cm3 total of distilled water and then dried over anhydrous magnesium sulphate, added with 0.5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 50 ° C. 6.7 g of crude product are thus obtained. This product is dissolved in 25 cm3 of boiling isopropanol.
• Phenoxy-3 aniline can be prepared according to the method described by F.ULLMANN and P. SPONAGEL, Annalen, 350, 83 (1906).
• Chloroformyl - 7 (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride is prepared according to the method described in European Patent No. 0 115 979.
• the solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C.
• the residue is dissolved in 750 cm3 of ethyl acetate.
• the solution obtained is washed 3 times with 800 cm3 in total of distilled water, 2 times with 600 cm3 in total with a saturated aqueous solution of sodium bicarbonate and 2 times with 600 cm3 in total with distilled water and then dried over anhydrous magnesium sulfate, supplemented with 0.5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C.
• the acid chloride hydrochloride from (+) (3-pyridyl) -3 1H, 3H pyrrolo [1,2-c] thiazole carboxylic-7 acid is prepared as follows: A suspension of 20.9 g of (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxylic-7 acid in a mixture of 52.1 g of thionyl chloride, 0.1 cm3 of dimethylformamide and 290 cm3 1,2-dichloroethane is heated to a temperature in the region of 80 ° C for 3 hours.
• the (+) (pyridyl-3) -3 1H, 3 H -pyrrolo [1,2-c] ethyl-7 thiazolecarboxylate can be prepared in the following way: To a suspension of 23.8 g of N acid -formyl (pyridyl-3) -2 thiazolidine-carboxylic-4- (2R, 4R) in 90 cm3 of 1,2-dichloroethane, added in 2 minutes, at a temperature between 20 and 27 ° C, 11, 2 g of triethylamine.
• the suspension obtained is stirred at a temperature in the region of 20 ° C for 1 hour and the solution obtained is added in 50 minutes at a temperature in the region of 20 ° C to a solution of 21 g of paratoluenesulfonyl chloride in 110 cm3 of dichloro- 1.2 ethane.
• a cloudy solution is obtained (solution A).
• the solution A previously prepared is added in 50 minutes at a temperature between 20 and 36 ° C.
• the suspension obtained is stirred for 1 hour and 40 minutes at a temperature in the region of 40 ° C and then for 20 minutes at a temperature in the region of 60 ° C.
• the suspension obtained is added with 100 cm 3 of distilled water.
• the organic phase is separated, washed 3 times with 300 cm3 in total of distilled water, 2 times with 300 cm3 in total of a saturated aqueous solution of sodium bicarbonate then 2 times with 300 cm3 in total of distilled water, dried over anhydrous magnesium sulfate, supplemented with 0.5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C. 25.6 g of crude product are obtained which is dissolved in 250 cm3 of ethyl acetate. The solution obtained is extracted 3 times with 300 cm3 in total of an aqueous 2N hydrochloric acid solution.
• the aqueous extracts are combined, washed with 250 cm3 of ethyl acetate and brought to a pH in the region of 8 by addition of sodium bicarbonate.
• the suspension obtained is extracted a first time with a mixture of 250 cm3 of diethyl ether and 250 cm3 of ethyl acetate and then 3 times with 450 cm3 in total of ethyl acetate.
• Ethyl 2,3-dichloro propionate can be prepared according to the method described in Japanese Patent No. 81,87531 [Chem. Abstr., 95, 203335, (1981)].
• N-formyl (pyridyl-3) -2 thiazolidinecarboxylic-4- (2R, 4R) acid can be obtained in the following way: To 420 cm3 of formic acid, it is added in 25 minutes at a temperature close to 10 ° C, 340 g of acetic anhydride. The solution obtained is stirred at a temperature in the region of 10 ° C for 30 minutes and then added in 50 minutes to a temperature in the region of 10 ° C of 233 g of (pyridyl-3) -2 thiazolidinecarboxylic-4- (2RS, 4R). The solution obtained is stirred at a temperature in the region of 10 ° C for 30 minutes and then in a temperature in the region of 20 ° C for 16 hours.
• the solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C.
• the residue obtained is suspended in 2600 cm3 of boiling ethanol.
• the suspension obtained is cooled to a temperature in the region of 4 ° C for 2 hours.
• the crystals which have appeared are filtered off, washed twice with 530 cm 3 in total of ethanol cooled to a temperature in the region of 4 ° C. and air dried. 245 g of product melting at 230 ° C. are thus obtained.
• 60 g of this product are dissolved in 540 cm3 of 50% aqueous ethanol at the boil.
• the solution obtained is cooled to a temperature close to 10 ° C for 2 hours.
• (3-pyridyl-2) thiazolidinecarboxylic acid-4 (2RS, 4R) can be prepared according to A.BANASHEK and M.I. SHCHUKINA, J. Gen. Chem. U.S.S.R., 31, 1374 (1961); Chem. Abstr. 55, 24739h, (1961).
• the solution obtained is filtered hot and cooled to a temperature in the region of 10 ° C and is brought to a pH in the region of 3.5 by addition of concentrated hydrochloric acid at a temperature between 10 and 15 ° C.
• the crystals which appear are separated by filtration, washed 3 times with 600 cm 3 in total of distilled water, 2 times with 160 cm 3 in total with ethanol and 2 times with 200 cm 3 in total with diethyl ether and then dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 20 ° C in the presence of potassium hydroxide pellets.
• 48 g of product are obtained which is dissolved in 1000 cm 3 of boiling ethanol; 0.5 g of bleaching black is added to the solution obtained and filtered hot.
• the filtrate obtained is cooled to a temperature in the region of 4 ° C for 2 hours.
• the crystals which appear are separated by filtration, washed twice with a total of 60 cm3 of ethanol cooled to a temperature in the region of 4 ° C. and then twice with 200 cm3 of diethyl ether and then dried under reduced pressure (20 mm of mercury ; 2.7 kPa) at a temperature in the region of 20 ° C in the presence of potassium hydroxide pellets.
• 42.5 g of (+) (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 acid are thus obtained in the form of yellow crystals melting at 210 ° C.
• (+) (3-pyridyl) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxylic-7 acid can be prepared according to the method described in European Patent No. 0 115 979.
• reaction mixture is washed 3 times with 600 cm 3 in total of distilled water.
• the organic phase is separated, dried over anhydrous magnesium sulfate, added with 0.5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 °. vs. 29.3 g of product are obtained which is dissolved in 500 cm 3 of ethyl acetate; 0.5 g of bleaching black and 30 g of silica (0.020-0.045 mm) are added to the solution obtained, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a similar temperature 60 ° C.
• N-formyl (pyridyl-3) -2 thiazolidinecarboxylic-4- (2R, 4R) acid can be prepared as indicated in Example 2.
• N- (3-benzoyl-phenyl) 2,3-dichloro-propionamide can be prepared as follows: To a solution of 29.6 g of 3-amino-benzophenone in 400 cm 3 of toluene, a mixture is added over 20 minutes to a temperature between 60 and 105 ° C, a solution of 24.2 g of 2,3-dichloro-propionyl chloride in 80 cm3 of toluene. The solution obtained is heated to a temperature in the region of 110 ° C for 3 hours and then is stirred at a temperature in the region of 20 ° C for 16 hours. The solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C.
• 3-amino benzophenone can be prepared according to R. GEIGY and W. KOENIGS, Ber., 18, 2400 (1885).
• the first 5 fractions from the elution with pure methylene chloride are eliminated.
• the following 9 fractions originating from the elution with a mixture of methylene chloride and methanol (99-1 by volume) are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a similar temperature 50 ° C.
• 9.4 g of crude product are thus obtained which are dissolved in 100 cm3 of boiling isopropanol.
• 0.5 g of bleaching black is added to the solution obtained and filtered hot.
• the filtrate obtained is cooled to a temperature in the region of 4 ° C for 16 hours.
• Aniline (4-chloro-phenoxy) -3 can be prepared according to K.IKAWA, J.Pharm. Soc. Jap., 79, 269 (1959).
• Chloroformyl-7 (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride is prepared according to the method described in European Patent No. 0 115 979.
• the residue is dissolved in 400 cm3 of methylene chloride.
• the solution obtained is washed 2 times with 200 cm3 in total of distilled water, 2 times with 200 cm3 in total of an aqueous solution of sodium hydroxide and 5 times with 500 cm3 in total of distilled water and then dried over sulphate of anhydrous magnesium, added with 0.5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 50 ° C. 7 g of crude product are thus obtained which are dissolved in 100 cm 3 of boiling acetonitrile. 0.5 g of bleaching black is added to the solution obtained and filtered hot.
• the filtrate is cooled to a temperature in the region of 4 ° C for 1 hour.
• the crystals which appear are separated by filtration, washed twice with a total of 20 cm 3 of acetonitrile cooled to a temperature in the region of 4 ° C. and twice with a total of 20 cm 3 of diethyl ether and then dried under reduced pressure (20 mm of mercury ; 2.7 kPa) at a temperature in the region of 20 ° C in the presence of potassium hydroxide pellets.
• the (2-methylphenoxy) -3 aniline can be prepared according to the method described in Dutch patent n ° 66/2994.
• Chloroformyl-7 (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride is prepared according to the method described in European Patent No. 0 115 979.
• the solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C.
• the residue obtained is dissolved in 350 cm3 of methylene chloride and the solution obtained is washed 2 times with 200 cm3 in total of distilled water, 2 times with 200 cm3 in total of an aqueous solution of sodium hydroxide N and 5 times with 500 cm3 in total of distilled water and then dried over anhydrous magnesium sulphate, added with 0.5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 50 ° C. 13 g of crude product are thus obtained.
• This product is dissolved in 50 cm3 of boiling acetonitrile.
• Aniline (3-methylphenoxy) -3 can be prepared according to K.IKAWA, J. Pharm. Soc. Jap., 75, 457 (1955); Chem. Abstr., 50, 2480 (1956).
• Chloroformyl-7 (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride is prepared according to the method described in European Patent No. 0 115 979.
• Aniline (4-methylphenoxy) -3 can be prepared according to the method described in Dutch Patent No. 66/2994.
• Chloroformyl-7 (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride is prepared according to the method described in European Patent No. 0 115 979.
• the solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C.
• the residue is dissolved in 400 cm 3 of methylene chloride.
• the solution obtained is washed with 100 cm3 of distilled water, twice with 200 cm3 in total of an aqueous sodium hydroxide solution, and 6 times with 600 cm3 in total with distilled water and then dried over anhydrous magnesium sulfate, supplemented with 0.5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 50 ° C. 7.8 g of crude product are thus obtained which is dissolved in 50 cm3 of boiling acetonitrile.
• Aniline (2-methoxy-phenoxy) -3 is prepared according to K. IKAWA, J. Pharm. Soc. Jap., 79, 1493 (1959); Chem. Abstr., 54, 10922 (1960).
• Chloroformyl-7 (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride is prepared according to the method described in European Patent No. 0 115 979.
• the solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 65 ° C.
• the residue is dissolved in 350 cm3 of methylene chloride.
• the solution obtained is washed twice with 200 cm3 in total of distilled water, 2 times with 200 cm3 in total of an aqueous sodium hydroxide solution, and 5 times with 750 cm3 in total of distilled water and then dried over sulphate anhydrous magnesium, added with 0.5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 50 ° C. 12 g of crude product are thus obtained which are dissolved in 50 cm3 of boiling acetonitrile.
• Aniline (3-methoxy-phenoxy) -3 can be prepared according to K.IKAWA, J. Pharm. Soc. Jap., 79, 1493 (1959).
• Chloroformyl-7 (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride is prepared according to the method described in European Patent No. 0 115 979.
• the solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 65 ° C.
• the residue is dissolved in 400 cm3 of methylene chloride and the solution obtained is washed 2 times with 200 cm3 in total of distilled water, 2 times with 200 cm3 in total of an aqueous solution of sodium hydroxide N and 5 times with 500 cm3 total distilled water and then dried over anhydrous magnesium sulfate, supplemented with 0.5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 50 ° C.
• Aniline (4-methoxy-phenoxy) -3 can be prepared according to K. IKAWA, J. Pharm., Soc., Jap., 79, 1493 (1959).
• Chloroformyl-7 (pyridyl-3) 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride is prepared according to the method described in European Patent No. 0 115 979.
• the residue is taken up in a mixture of 150 cm3 of an aqueous solution of sodium hydroxide N and 350 cm3 of methylene chloride.
• the organic phase is separated, washed 5 times with 500 cm 3 in total of distilled water and then dried over anhydrous magnesium sulfate, added with 0.5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury ; 2.7 kPa) at a temperature in the region of 50 ° C. 9 g of crude product are thus obtained which are suspended in 30 cm3 of a mixture of cyclohexane and ethyl acetate (50-50 by volume).
• the crystals which appear are separated by filtration, washed twice with 10 cm 3 in total of a mixture of cyclohexane and ethyl acetate (50-50 by volume) and then dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 20 ° C in the presence of potash tablets. This gives 6.6 g of product melting at 148 ° C. which is dissolved in 50 cm3 of boiling acetonitrile; 0.5 g of bleaching black is added to the solution obtained and filtered hot. The filtrate is cooled to a temperature in the region of 4 ° C for 16 hours.
• 2-methoxy-5-phenoxy aniline can be obtained according to G. SCHIEMANN and W. WINKELMULLER, J. Prakt. Chem., 135, 101 (1932).
• Chloroformyl-7 (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride is prepared according to the method described in European Patent No. 0 115 979.
• the solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C.
• the residue is dissolved in 300 cm3 of methylene chloride.
• the solution obtained is washed 2 times with 500 cm3 in total of distilled water, 2 times with 300 cm3 in total of an aqueous solution of sodium hydroxide and 2 times with 500 cm3 in total of distilled water and then dried over sulphate of anhydrous magnesium, added with 0.5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C. 15.8 g of crude product are thus obtained which are dissolved in 100 cm 3 of boiling acetonitrile.
• Aniline (2-pyridyl-oxy) -3 can be prepared according to the method described in German Patent No. 3,139,457.
• Chloroformyl-7 (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride is prepared according to the method described in European Patent No. 0 115 979.
• the solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C.
• the residue is dissolved in 300 cm3 of methylene chloride.
• the solution obtained is washed twice with 300 cm3 in total of distilled water, twice with 300 cm3 in total of an aqueous sodium hydroxide solution, and twice with 300 cm3 in total of distilled water and then dried over sulphate anhydrous magnesium, added with 0.5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C. 8.2 g of crude product are thus obtained which is dissolved in 50 cm3 of boiling acetonitrile.
• Chloroformyl-7 (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride is prepared according to the method described in European Patent No. 0 115 979.
• the (3-pyridyl-oxy) -3 aniline is prepared as follows: To a suspension of 16.2 g of (3-pyridyl-oxy) -3 nitrobenzene and 37.5 g of iron powder in 40 cm3 of distilled water heated to a temperature in the region of 90 ° C, 0.4 g of ferric chloride is added at a temperature between 90 and 98 ° C. The suspension obtained is heated to a temperature in the region of 98 ° C for 1 hour and 15 minutes and then is stirred at a temperature in the region of 20 ° C for 16 hours, supplemented with 550 cm3 of methylene chloride and 75 cm3 of distilled water and filtered.
• the organic phase is separated, dried over anhydrous magnesium sulfate, added with 0.5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 °. vs. 13.1 g of crude oil are thus obtained which is chromatographed on a column 6 cm in diameter containing 450 g of silica (0.02-0.045 mm). Eluted with mixtures of ethyl acetate and cyclohexane under a pressure of 0.4 bar (40 kPa), collecting fractions of 150 cm3.
• the first 15 fractions from elution with a mixture of ethyl acetate and cyclohexane (50-50 by volume) are eliminated.
• the next 5 fractions from the elution with a mixture of ethyl acetate and cyclohexane (50-50 by volume) and the next 5 fractions from the elution with pure ethyl acetate are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 60 "C.
• the (3-pyridyl-oxy) -3 nitrobenzene is prepared as follows: A solution of 47.5 g of 3-hydroxy pyridine and 33 g of potassium hydroxide pellets in 400 cm3 of ethanol is heated to a neighboring temperature 80 ° C for 1 hour. The solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 70 ° C and the residue is dissolved in 350 cm3 of dimethyl sulfoxide. 101 g of 3-bromo-nitrobenzene and 0.1 g of copper powder are added to the solution obtained, then it is heated under a stream of dry nitrogen to a temperature in the region of 160 ° C. for 1 hour.
• the reaction mixture obtained is cooled to a temperature in the region of 20 ° C , supplemented with 2500 cm3 of distilled water and 500 cm3 of methylene chloride.
• the organic phase is separated and the aqueous phase is extracted twice with 1000 cm 3 in total of methylene chloride.
• the organic extracts are combined, washed 3 times with 1500 cm 3 in total of distilled water, dried over anhydrous magnesium sulfate, added with 0.5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury ; 2.7 kPa) at a temperature in the region of 60 ° C.
• the crude oil obtained (77 g) is distilled under reduced pressure. 41.8 g of (3-pyridyloxy) -3 nitrobenzene are thus obtained in the form of an orange liquid boiling at 165-175 ° C under 0.1 mm of mercury (13.5 Pa).
• the residue is dissolved in 500 cm3 of methylene chloride and the solution obtained is washed 2 times with 200 cm3 in total of distilled water, 4 times with 800 cm3 in total of an aqueous solution of sodium hydroxide N and 5 times with 500 cm3 total of distilled water and then dried over anhydrous magnesium sulphate, added with 0.5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 50 ° C.
• the product obtained is chromatographed on a column 8.5 cm in diameter containing 1 kg of silica (0.02-0.045 mm).
• Elution is carried out with mixtures of cyclohexane and ethyl acetate under a pressure of 0.4 bar (40 kPa), collecting 500 cm 3 fractions.
• the first 10 fractions from the elution with a mixture of ethyl acetate and cyclohexane (60-40 by volume) and the next 5 fractions from the elution with a mixture of ethyl acetate and of cyclohexane (80-20 by volume) are eliminated.
• 3-amino benzophenone can be prepared according to R. GEIGY and W. KOENIGS, Ber., 18, 2400 (1885).
• Chloroformyl-7 (pyridyl-3) - 3 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride is prepared according to the method described in European Patent No. 0 115 979.
• the solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C.
• the residue is dissolved in 300 cm3 of methylene chloride.
• the solution obtained is washed twice with 300 cm3 in total of distilled water, twice with 300 cm3 in total of a 2N aqueous sodium hydroxide solution, and twice with 300 cm3 in total of distilled water and then dried over sulphate anhydrous magnesium, supplemented with 0.5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C. 9.8 g of crude product are thus obtained which is dissolved in 250 cm3 of boiling acetonitrile.
• the 3-amino-chloro-4'benzophenone can be obtained according to FE KING, TJ KING AND IHM MUIR, J. Chem. Soc., 5, (1946).
• Chloroformyl-7 (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride is prepared according to the method described in European Patent No. 0 115 979.
• the solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C.
• the residue is dissolved in 300 cm3 of methylene chloride.
• the solution obtained is washed twice with 300 cm3 in total of distilled water, twice with 300 cm3 in total of an aqueous solution of sodium hydroxide and twice with 300 cm3 in total of distilled water and then dried over sulphate of anhydrous magnesium, added with 0.5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C. 9 g of crude product are thus obtained which are dissolved in 75 cm 3 of boiling acetonitrile.
• Chloroformyl-7 (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride is prepared according to the method described in European Patent No. 0 115 979.
• 3-amino-3'-methyl benzophenone can be prepared as follows: To a suspension of 6.8 g of 3-methyl-3-nitro-benzophenone in a mixture of 80 cm3 of ethanol and 30 cm3 of concentrated hydrochloric acid, 19 g of stannous chloride in the form of a dihydrate are added over 10 minutes at a temperature between 40 and 80 ° C. The solution obtained is heated to a temperature in the region of 85 ° C for 3 hours and then is stirred at a temperature in the region of 20 ° C for 16 hours. The solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C. The residue is suspended in 300 cm3 of distilled water.
• the suspension obtained is added with stirring at a temperature in the region of 20 ° C to 100 cm3 of an aqueous solution of ION sodium hydroxide solution and is extracted 3 times with 550 cm3 in total of diethyl ether.
• the ethereal extracts are combined, washed twice with 300 cm3 in total of distilled water and then dried over anhydrous magnesium sulfate, added with 0.5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury ; 2.7 kPa) at a temperature in the region of 50 ° C. 5.7 g of 3-amino-3'-methylphenophenone are thus obtained in the form of yellow crystals, melting at 110 ° C.
• 3-methyl-3-nitro-benzophenone can be obtained from K. DEY, C. EABORN and D.R.M. WALTON, Organometal Chem. Syn., 1, 151 (1971).
• the solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 60 ° C.
• the residue is dissolved in 200 cm3 of methylene chloride and the solution obtained is washed 2 times with 200 cm3 in total of distilled water, 2 times with 200 cm3 in total of an aqueous solution of sodium hydroxide N and 3 times with 300 cm3 total of distilled water and then dried over anhydrous magnesium sulphate, added with 0.5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 50 ° C.
• the filtrate obtained is cooled to a temperature in the region of 4 ° C for 2 hours.
• the crystals which appear are separated by filtration, washed twice with 15 cm3 in total of acetonitrile cooled to a temperature in the region of 4 ° C. and twice with 20 cm3 in total of diethyl ether and then dried under reduced pressure (20 mm of mercury ; 2.7 kPa) at a temperature in the region of 20 ° C in the presence of potassium hydroxide pellets.
• Amino-3-methoxy-4 'benzophenone can be prepared according to H. OELSCHLAGER, Arzneim. Forsch., 8, 532 (1958).
• Chloroformyl-7 (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride is prepared according to the method described in European Patent No. 0 115 979.
• the solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C.
• the residue is dissolved in 350 cm3 of methylene chloride and the solution obtained is washed 2 times with 200 cm3 in total of distilled water, 2 times with 200 cm3 in total of a 2N aqueous sodium hydroxide solution and 3 times with 450 cm3 total of distilled water and then dried over anhydrous magnesium sulphate, added with 0.5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 50 ° C.
• the product obtained is chromatographed on a column 8 cm in diameter containing 500 g of silica (0.02-0.045 mm). Elution is carried out with mixtures of ethyl acetate and methanol under a pressure of 0.4 bar (40 kPa), collecting 500 cm 3 fractions. The first 19 fractions from the elution with pure ethyl acetate are eliminated.
• the (3-amino-benzoyl) -3 pyridine can be obtained according to T. HOGBERG, B. ULFF, A.L. RENYI and S.B. ROSS, J. Med. Chem., 24, 1499 (1981).
• Chloroformyl-7 (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride is prepared according to the method described in European patent No. 0 115 979.
• the solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C.
• the residue is dissolved in 200 cm3 of methylene chloride and the solution obtained is washed 2 times with 200 cm3 in total of distilled water, 2 times with 200 cm3 in total of an aqueous solution of sodium hydroxide N and 3 times with 300 cm3 total of distilled water and then dried over anhydrous magnesium sulphate, added with 0.5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 50 ° C.
• the filtrate obtained is cooled to a temperature in the region of 4 ° C for 16 hours.
• the crystals which have appeared are separated by filtration, washed twice with 6 cm3 in total of acetonitrile cooled to a temperature in the region of 4 ° C. and twice with 20 cm3 in total of diethyl ether and then dried under reduced pressure (20 mm of mercury ; 2.7 kPa) at a temperature in the region of 20 ° C in the presence of potassium hydroxide pellets.
• Chloroformyl-7 (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride is prepared according to the method described in European Patent No. 0 115 979.
• the (3-amino-benzoyl) -2 pyridine can be prepared as follows: To a suspension of 19 g of (3-nitro-benzoyl) -2 pyridine in 360 cm3 of a solution of 3.7N hydrochloric ethanol, 63 g of stannous chloride, in the form of a dihydrate, are added over 45 minutes at a temperature in the region of 3 ° C. The suspension obtained is stirred at a temperature in the region of 4 ° C for 1 hour and 30 minutes, at a temperature in the region of 20 ° C for 1 hour and 30 minutes and then at a temperature in the region of 80 ° C for 1 hour and 30 minutes.
• the solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 50 ° C.
• the residue is taken up in 200 cm3 of distilled water.
• the aqueous solution is brought to a pH in the region of 11 by addition of an aqueous solution of ION sodium hydroxide at a temperature in the region of 25 ° C., saturated with sodium chloride and is then extracted 3 times with 600 cm 3 in total of diethyl ether .
• the ethereal extracts are combined, washed 3 times with 300 cm3 in total of a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, added with 0.5 g of bleaching black, filtered and concentrated to dryness under pressure reduced (20 mm of mercury; 2.7 kPa) at a temperature close to 40 ° C. 15.8 g of crude product are obtained which are chromatographed on a column 8 cm in diameter containing 500 g of silica (0.02-0.045 mm). Eluted with a mixture of cyclohexane and ethyl acetate (50-50 by volume) under a pressure of 0.4 bar (40 kPa), collecting 400 cm3 fractions.
• the first 7 fractions are eliminated.
• the following 7 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 50 ° C.
• 12 g of (3-amino benzoyl) -2 pyridine are obtained in the form of a red oil used crude in the subsequent syntheses.
• (3-Nitro-benzoyl) -2 pyridine can be prepared according to A.R. HANDS and A.R. KATRITZKY, J. Chem. Soc., 1754 (1958).
• the solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C.
• the residue is dissolved in 350 cm3 of methylene chloride.
• the solution obtained is washed twice with 300 cm3 in total of distilled water, twice with 300 cm3 in total of a 2N aqueous sodium hydroxide solution, and twice with 300 cm3 in total of distilled water and then dried over sulphate anhydrous magnesium, supplemented with 0.5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C. 10 g of crude product are thus obtained which is dissolved in 250 cm3 of boiling acetonitrile.
• Chloroformyl-7 (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride is prepared according to the method described in European Patent No. 0 115 979.
• the (thénoyl-2) -3 aniline can be prepared as follows: To a suspension of 6.8 g of (thénoyl-2) -3 nitrobenzene in 130 cm3 of a solution of hydrochloric ethanol 3.7N, one add in 40 minutes, at a temperature in the region of 4 ° C., 22.8 g of stannous chloride in the dihydrate state. After stirring at a temperature in the region of 4 ° C for 1 hour and then at a temperature in the region of 20 ° C for 1 hour, the solution obtained is heated to a temperature in the region of 78 ° C for 1 hour. The solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 50 ° C.
• the residue obtained is taken up in a mixture of 50 cm3 of distilled water and 100 cm3 of diethyl ether to which is added, at a temperature in the region of 15 ° C, 130 cm3 of a 10N aqueous sodium hydroxide solution.
• the organic phase is separated and the aqueous phase is extracted 4 times with 400 cm 3 in total of diethyl ether.
• the ethereal extracts are combined, washed 3 times with 300 cm3 in total of distilled water, dried over anhydrous magnesium sulfate, added with 0.5 g of bleaching black, and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 5.7 g of (thenoyl-3) -2 aniline are thus obtained in the form of yellow crystals, melting at 105 ° C.
• (3-Thenoyl-3) nitrobenzene can be prepared according to R. GONCALVES, M.R. KEGELMAN and E.V. BROWN, J. Org. Chem., 17, 705 (1952).
• the filtrate is cooled to a temperature in the region of 4 ° C for 16 hours.
• the crystals which appear are separated by filtration, washed 3 times with 45 cm3 in total of acetonitrile and 3 times with 90 cm3 in total of diethyl ether and then dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 20 ° C in the presence of potash tablets. 0.3 g of product melting at 140 ° C. is thus obtained.
• the mother liquors of crystallization are concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C.
• Anilino-3 aniline can be prepared according to H. WIELAND and W. RHEINHEIMER, Annalen, 423, 1 (1931).
• Chloroformyl-7 (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride is prepared according to the method described in European Patent No. 0 115 979.
• the solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C.
• the residue is dissolved in 250 cm3 of methylene chloride.
• the solution obtained is washed twice with 160 cm3 in total of distilled water, twice with 200 cm3 in total with an aqueous solution of sodium hydroxide and 5 times with 500 cm3 in total with distilled water and then dried over sulphate of anhydrous magnesium, added with 0.5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 50 ° C. 5 g of crude product are thus obtained which is dissolved in 50 cm3 of boiling acetonitrile.
• Benzyl-3 aniline can be prepared according to H. OELSCHLAGER, Chem. Ber., 89, 2025 (1956).
• Chloroformyl-7 (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride is prepared according to the method described in European Patent No. 0 115 979.
• the solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C.
• the residue is dissolved in 300 cm3 of methylene chloride.
• the solution obtained is washed twice with 300 cm3 in total of distilled water, twice with 300 cm3 in total of a 2N aqueous sodium hydroxide solution, and twice with 300 cm3 in total of distilled water and then dried over sulphate anhydrous magnesium, supplemented with 0.5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C. 11.5 g of crude product are thus obtained which is dissolved in 110 cm3 of boiling acetonitrile.
• Phenylthio-3 aniline can be prepared according to the method described in Belgian Patent No. 765,558.
• Chloroformyl-7 (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride is prepared according to the method described in European Patent No. 0 115 979.
• the solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 50 ° C.
• the residue is dissolved in 400 cm3 of methylene chloride.
• the solution obtained is washed with 100 cm3 of distilled water, with 100 cm3 of an aqueous 4N sodium hydroxide solution, and 3 times with 450 cm3 in total of distilled water and then dried over anhydrous magnesium sulphate, added with 0, 5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 50 ° C. 8.2 g of crude product are thus obtained which is dissolved in 250 cm3 of boiling butanol-1.
• the crystals which appear are separated by filtration, washed twice with 10 cm 3 in total of butanol-1 cooled to a temperature in the region of 4 ° C, 3 times in 30 cm3 in total of ethanol cooled to a temperature in the region of 4 ° C and 3 times per 60 cm3 in total of diethyl ether and then dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 20 ° C in the presence of potassium hydroxide pellets.
• Chloroformyl-7 (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride is prepared according to the method described in European Patent No. 0 115 979.
• the 3-amino-dimethylamino-4 'benzophenone can be prepared as follows: To a suspension of 11.4 g of 4-dimethylamino-3-nitro-benzophenone in a mixture of 45 cm 3 of concentrated hydrochloric acid and 120 cm 3 ethanol, 29.3 g of stannous chloride in the form of a dihydrate are added over 35 minutes, at a temperature between 44 and 79 ° C. The solution obtained is heated to a temperature in the region of 79 ° C for 3 hours. The suspension obtained is concentrated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 50 ° C.
• the residue obtained is suspended in 350 cm3 of distilled water and the suspension obtained is added, at a temperature in the region of 5 ° C, to 100 cm3 of a solution aqueous sodium hydroxide ION and then stirred at a temperature in the region of 20 ° C for 30 minutes.
• the crystals which appear are separated by filtration, washed 3 times with 60 cm 3 in total of distilled water and air dried.
• the crude product obtained is dissolved in 30 cm3 of boiling isopropanol and the solution obtained is cooled to a temperature in the region of 4 ° C for 2 hours.
• the crystals which appear are separated by filtration, washed twice with 20 cm 3 in total of isopropanol cooled to a temperature in the region of 4 ° C.
• Dimethylamino-4 '3-nitro-benzophenone can be prepared according to R.C. SHAH, R.K. DESHPANDE and J.S. CHAUBAL, J. Chem. Soc., 642 (1932).
• the solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C. the residue is dissolved in 300 cm3 of methylene chloride.
• the solution obtained is washed with 100 cm3 of distilled water, with 100 cm3 of an aqueous solution of sodium hydroxide and 5 times with 500 cm3 in total of distilled water and then dried over anhydrous magnesium sulphate, added with 0.5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 50 ° C. 6.5 g of crude product are thus obtained which is dissolved in 300 cm3 of boiling acetonitrile.
• the solution 0.5 g of bleaching black is added and filtered hot.
• the filtrate is cooled to a temperature in the region of 4 ° C for 16 hours.
• the crystals which have appeared are separated by filtration, washed twice with a total of 20 cm 3 of acetonitrile cooled to a temperature in the region of 4 ° C. and twice with a total of 40 cm 3 of diethyl ether and then dried under reduced pressure (20 mm of mercury ; 2.7 kPa) at a temperature in the region of 20 ° C in the presence of potassium hydroxide pellets.
• (3-amino-benzoyl) -4 pyridine can be prepared according to F. SAUTER, P. STANETTY and A. MESBAH, Monatsh., 107, 1449 (1976).
• Chloroformyl-7 (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride is prepared according to the method described in European Patent No. 0 115 979.
• the solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 50 ° C.
• the residue is dissolved in 250 cm3 of methylene chloride.
• the solution obtained is washed twice with 200 cm3 in total of distilled water, with 100 cm3 of a 2N aqueous sodium hydroxide solution, and 3 times with 300 cm3 in total of distilled water and then dried over anhydrous magnesium sulfate, added with 0.5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 45 ° C. 8.3 g of crude product are thus obtained which is dissolved in 50 cm3 of boiling acetonitrile.
• the solution obtained is added with 0.5 g of bleaching black and filtered hot.
• the filtrate is cooled to a temperature in the region of 4 ° C for 1 hour.
• the crystals which appear are separated by filtration, washed twice with 30 cm3 in total of acetonitrile cooled to a temperature in the region of 4 ° C and twice with 60 cm3 in total of diethyl ether and then dried under reduced pressure (20 mm of mercury ; 2.7 kPa) at a temperature in the region of 20 ° C in the presence of potassium hydroxide pellets.
• Amino-3 chloro-4 benzophenone can be prepared according to D. MARON and C. FOX, Ber., 47, 2774 (1914).
• the solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 50 ° C.
• the residue is dissolved in 250 cm3 of methylene chloride.
• the solution obtained is washed with 100 cm3 of distilled water, twice with 200 cm3 in total of an aqueous solution of sodium hydroxide N and 3 times with 300 cm3 in total with distilled water and then dried over anhydrous magnesium sulfate, added 0.5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 45 ° C. 6.8 g of crude product are thus obtained which is dissolved in 60 cm3 of boiling acetonitrile.
• Chloroformyl-7 (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride is prepared according to the method described in European Patent No. 0 115 979.
• 3-amino-2-methoxy-benzophenone can be prepared as follows: To a suspension of 3.9 g of 2-methoxy-3-nitro-3 'benzophenone in a mixture of 40 cm3 of ethanol and 15.2 cm3 concentrated hydrochloric acid (11.7N) heated to a temperature in the region of 62 ° C, 10.3 g of stannous chloride in the form of a dihydrate are added over 5 minutes at a temperature between 62 and 66 ° C.
• the solution obtained is heated to a temperature in the region of 80 ° C for 4 hours, added with 1 g of stannous chloride in the form of a dihydrate and heated to a temperature in the region of 80 ° C for an additional 1 hour and then stirred at a temperature close to at 20 ° C for 16 hours.
• the solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 50 ° C.
• the residue is dissolved in 40 cm3 of distilled water and the solution obtained is brought, keeping the temperature in the region of 10 ° C, to a pH in the region of 13 by adding 50 cm3 of an aqueous 10N sodium hydroxide solution and then is extracted 3 times with 150 cm3 in total of methylene chloride.
• 2-methoxy-3-nitro-benzophenone can be prepared as follows: A suspension of 3.5 g of 2-hydroxy-3-nitro-benzophenone, 4 g of potassium carbonate and 4.2 g of methyl iodide in 100 cm3 of acetone is heated to a temperature in the region of 56 ° C. for 16 hours. The solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. The solid obtained is dissolved in a mixture of 80 cm3 of distilled water and 50 cm3 of ethyl acetate. The organic phase is separated and the aqueous phase is extracted twice with 100 cm 3 in total of ethyl acetate.
• 2-hydroxy-3-nitro benzophenone can be obtained according to I.H. BOWEN and J.R. LEWIS, J. Chem. Soc., Perkin Trans. I, 683 (1972).
• the solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 50 ° C.
• the residue is dissolved in 500 cm3 of chloride methylene.
• the solution obtained is washed 4 times with 650 cm 3 in total of distilled water, then dried over anhydrous magnesium sulfate, added with 0.5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 50 ° C. This gives 13.5 g of crude product which is dissolved in 300 cm3 of boiling acetonitrile. 0.5 g of bleaching black is added to the solution obtained and filtered hot.
• the filtrate is cooled to a temperature in the region of 4 ° C for 16 hours.
• the crystals which appear are separated by filtration, washed 3 times with 60 cm 3 in total of acetonitrile and then dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 20 ° C. in the presence of potassium hydroxide pellets.
• 7.1 g of N- (cinnamoyl-3 phenyl) (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 are thus obtained in the form of beige crystals, melting at 190 ° C.
• Cinnamoyl-3 aniline can be prepared according to W. DAVEY and JR GWILT, J. C hem., Soc., 1008 (1957).
• Chloroformyl-7 (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride is prepared according to the method described in European Patent No. 0 115 979.
• the solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C.
• the residue is dissolved in 300 cm3 of nethylene chloride.
• the solution obtained is washed twice with 300 cm3 in total of distilled water, twice with 300 cm3 in total with a saturated aqueous solution of sodium bicarbonate and twice with 300 cm3 in total with water distilled and then dried over anhydrous magnesium sulfate, supplemented with 0.5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C.
• Ethyl (3-amino benzoyl) -2 benzoate can be obtained according to the method described in German patent 279,201 (Beilstein, 14, 661).
• Chloroformyl-7 (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride is prepared according to the method described in European Patent No. 0 115 979.
• the filtrate is cooled to a temperature in the region of 4 ° C for 3 days.
• the crystals which appear are separated by filtration, washed 3 times with 30 cm3 in total of a mixture of butanol-1 and dimethylformamide (35-65 by volume), 3 times with 90 cm3 in total of ethanol and 3 times with 90 cm3 in total of diethyl ether and then dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 20 ° C in the presence of potassium hydroxide pellets.
• the solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C.
• the residue is dissolved in 300 cm3 of methylene chloride.
• the solution obtained is washed 2 times with 300 cm3 in total of distilled water, 2 times with 300 cm3 in total of an aqueous sodium hydroxide solution and 2 times with 300 cm3 in total of distilled water and then dried over anhydrous magnesium sulfate, supplemented with 0.5 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C. 10.1 g of crude product are thus obtained which is dissolved in 80 cm 3 of boiling acetonitrile.
• Chloroformyl-7 (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride is prepared according to the method described in European Patent No. 0 115 979.
• the 3-amino-4-dimethylamino-benzophenone is prepared as follows: Hydrogen is bubbled for 3 hours at a temperature close to 20 ° C. in a suspension of 5.4 g of 4-dimethylamino-3-nitro-benzophenone and 2.7 g of activated Raney nickel in 100 cm3 of ethyl acetate. The suspension is filtered and the filtrate is concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C. 5 g of product are thus obtained which is dissolved in 200 cm 3 of a mixture of ethyl acetate and cyclohexane (40-60 by volume).
• Dimethylamino-4 nitrc-3 benzophenone is prepared according to D. MARON and C. FOX, Ber., 47, 2774 (1914).
• the present invention also relates to medicaments consisting of a product of general formula (I), in free form or in the form of an addition salt with a pharmaceutically acceptable acid, in the pure state or in the form of a composition in which it is associated with any other pharmaceutically compatible product, which may be inert or physiologically active.
• the medicaments according to the invention can be used orally, parenterally, rectally or topically.
• compositions for oral administration tablets, pills, powders (especially in gelatin capsules or cachets) or granules can be used.
• the active product according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica.
• these compositions can also include substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a colorant, a coating (dragees) or a varnish.
• compositions for oral administration there may be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or oil paraffin.
• inert diluents such as water, ethanol, glycerol, vegetable oils or oil paraffin.
• These compositions can also comprise substances other than diluents, for example wetting products, sweeteners, thickeners, flavorings or stabilizers.
• the sterile compositions for parenteral administration may preferably be aqueous or non-aqueous solutions, suspensions or emulsions.
• solvent or vehicle water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents, can be used.
• compositions can also contain adjuvants, in particular wetting agents, isotonizers, emulsifiers, dispersants and stabilizers.
• Sterilization can be done in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in a sterile injectable medium.
• compositions for rectal administration are suppositories or rectal capsules, which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.
• compositions for topical administration can be, for example, creams, ointments, lotions, eye drops, mouthwashes, nasal drops or aerosols.
• the products according to the invention are particularly useful in the treatment of all pathological conditions in which PAF-acether can be incriminated directly or indirectly, in particular allergic, inflammatory and digestive system disorders such as ulcers , colitis and intestinal damage caused by radiation or endotoxin shock.
• the doses depend on the desired effect and on the duration of the treatment; they are generally between 25 and 300 mg per day orally, intravenously or by inhalation for an adult in one or more doses.
• the doctor will determine the dosage he considers most appropriate based on age, weight and all other factors specific to the subject to be treated.
• An injectable solution containing 5 mg of active product having the following composition is prepared according to the usual technique.

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• Animal Behavior & Ethology (AREA)
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• General Chemical & Material Sciences (AREA)
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• Public Health (AREA)
• Pharmacology & Pharmacy (AREA)
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• Hematology (AREA)
• Diabetes (AREA)
• Pain & Pain Management (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
• Plural Heterocyclic Compounds (AREA)
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• 1986
  • 1986-07-04 FR FR8609728A patent/FR2601015B1/fr not_active Expired
• 1987
  • 1987-07-02 ES ES87401551T patent/ES2015070B3/es not_active Expired - Lifetime
  • 1987-07-02 IL IL83066A patent/IL83066A/xx not_active IP Right Cessation
  • 1987-07-02 AU AU75047/87A patent/AU597996B2/en not_active Ceased
  • 1987-07-02 IE IE176787A patent/IE60743B1/en not_active IP Right Cessation
  • 1987-07-02 MX MX719187A patent/MX173398B/es unknown
  • 1987-07-02 HU HU873009A patent/HU198727B/hu not_active IP Right Cessation
  • 1987-07-02 PT PT85235A patent/PT85235B/pt not_active IP Right Cessation
  • 1987-07-02 BG BG080408A patent/BG47038A3/xx unknown
  • 1987-07-02 BG BG088453A patent/BG47498A3/xx unknown
  • 1987-07-02 EP EP87401551A patent/EP0253711B1/de not_active Expired - Lifetime
  • 1987-07-02 PL PL1987266582A patent/PL149434B1/pl unknown
  • 1987-07-02 ZA ZA874814A patent/ZA874814B/xx unknown
  • 1987-07-02 AT AT87401551T patent/ATE53037T1/de not_active IP Right Cessation
  • 1987-07-02 CS CS875013A patent/CS262692B2/cs unknown
  • 1987-07-02 TN TNTNSN87083A patent/TNSN87083A1/fr unknown
  • 1987-07-02 JP JP62164101A patent/JPS6322589A/ja active Pending
  • 1987-07-02 NO NO872779A patent/NO170419C/no unknown
  • 1987-07-02 KR KR1019870007043A patent/KR880001681A/ko not_active Application Discontinuation
  • 1987-07-02 FI FI872931A patent/FI84727C/fi not_active IP Right Cessation
  • 1987-07-02 CA CA000541133A patent/CA1294966C/fr not_active Expired - Lifetime
  • 1987-07-02 MA MA21264A patent/MA21027A1/fr unknown
  • 1987-07-02 NZ NZ220929A patent/NZ220929A/xx unknown
  • 1987-07-02 SU SU874202952A patent/SU1528323A3/ru active
  • 1987-07-02 DD DD87304534A patent/DD263772A5/de not_active IP Right Cessation
  • 1987-07-02 PL PL1987279923A patent/PL149903B1/pl unknown
  • 1987-07-02 DK DK340087A patent/DK340087A/da not_active Application Discontinuation
  • 1987-07-02 DE DE8787401551T patent/DE3762861D1/de not_active Expired - Fee Related
  • 1987-07-02 US US07/069,520 patent/US4783472A/en not_active Expired - Fee Related
• 1988
  • 1988-07-14 SU SU884356106A patent/SU1588284A3/ru active
• 1990
  • 1990-05-24 GR GR89400251T patent/GR3000502T3/el unknown

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